Abnormal Food Timing and Circadian Dyssynchrony in Alcohol Induced Colon Carcinogenesis

摘要 结直肠癌(CRC)是美国癌症死亡的第二大原因。CRC的风险是 与现代生活方式紧密相连。酒精在我们的社会中被普遍使用，是一个公认的危险因素。 适用于癌前病变(息肉)和结肠癌病变。然而，这一知识并没有 转化为我们目前对结直肠癌的风险分层，因为酒精诱导的致癌过程不是 这是可预见的。粘膜炎症是一种公认的调节酒精诱导效应的机制。 肠道组织损伤。炎症在结直肠癌的发病机制中也起着重要作用。影响因素 在酒精环境下促进促肿瘤炎症状态是未知的。由于CRC只出现在 酒精使用者中的一小部分，单靠酒精可能不足以启动肿瘤过程 还需要额外的协因数。其中一个因素是昼夜节律失调，这是另一种现代生活方式 习惯，被证明与结直肠癌的风险增加有关。此外，我们已经表明， 昼夜节律加剧了酒精引起的肠道炎症。我们假设昼夜节律的改变 错误的进食节律(不正常的进食)是酒精诱发的一个重要决定因素 肠粘膜炎症与癌变。我们的初步数据支持我们的假设，并表明 不正常的饮食模式加速了酒精诱导的结直肠癌小鼠模型的息肉。在目标1中，我们将 在收集的组织中建立与酒精±异常进食模式相关的炎症特征 来自我们的动物实验。在这里，我们在结肠建立了一种促进癌症的炎症状态， 由rna-seq检测并通过免疫染色校准，与酒精或异常饮食习惯有关，或 他们的组合。然后，我们将确定酒精±延迟进食模式(4种情况)在 人类AIM 2的中枢和外周昼夜节律与结肠癌发生和粘膜标记物 目标3.在每次干预后，受试者将接受(1)测量的中心昼夜节律的评估 (2)用时钟测量肠道昼夜节律 口腔黏膜细胞的基因表达；以及(3)乙状结肠镜检查结肠粘膜样本以评估 炎症和致癌标记物以及微生物区系。这项提案将把进食延迟定义为 促进酒精诱导的结肠损伤导致癌变的因素，并将提供一个范式的转变 我们对酒精致癌促进作用的机制以及风险分层的理解 酒精饮用者。

Abstract Colorectal cancer (CRC) is the second leading cause of cancer mortality in the US. CRC's risk is closely linked to the modern lifestyle. Alcohol is commonly used in our society and is an established risk factor for both pre-cancerous (polyp) and cancerous lesions of the colon. However this knowledge has not been translated to our current risk stratifications for CRC as the process of alcohol-induced carcinogenesis is not predictable. Mucosal inflammation is a well-established mechanism that mediates the effect of alcohol induced tissue injury in the intestine. Inflammation also plays a crucial role in pathogenesis of CRC. Factors that promote a pro-tumorigenic inflammatory state in the setting of alcohol are unknown. Since CRC occurs only in a small subset of alcohol users, alcohol alone may not be sufficient to start the neoplastic process and additional cofactors are required. One such factor is circadian dysrhythmia that is another modern lifestyle habit, shown to be associated with an increased risk of CRC. Further, we have shown that disruption of circadian rhythm exacerbates alcohol-induced intestinal inflammation. We hypothesize that altered circadian rhythms due to “wrong-time” eating (abnormal eating) are an important determinant in alcohol induced intestinal mucosal inflammation and carcinogenesis. Our preliminary data supports our hypothesis and shows that abnormal eating patterns accelerate alcohol-induced polyposis in a mouse model of CRC. In Aim 1, we will establish the inflammatory profiles associated with alcohol ± abnormal eating patterns in the tissues collected from our animal experiments. Here, we establish a cancer-promoting inflammatory state in the colon, determined by RNA-seq and calibrated by immunostaining, linked to alcohol or abnormal eating patterns or their combination. We will then determine the effect of alcohol ± delayed eating patterns (4 conditions) in humans on central and peripheral circadian rhythms in Aim 2, and colon carcinogenesis and mucosal markers in Aim 3. After each intervention, subjects will undergo (1) assessment of central circadian rhythm measured by the dim light melatonin onset (DLMO); (2) assessment of intestinal circadian rhythm measured by clock gene expression in buccal mucosal cells; and (3) sigmoidoscopy sampling of the colon mucosa to assess inflammatory and carcinogenesis markers as well as microbiota. This proposal will identify delayed eating as a promoting factor for alcohol-induced colon injury leading to carcinogenesis, and will provide a paradigm shift in our understanding of the mechanisms underlying alcohol cancer promoting effects, as well as risk stratification of alcohol drinkers.